(Hetero) aryl-sulfonamide derivatives, their preparation and their use as factor XA inhibitors

ABSTRACT

A compound of formula (I),                    
     or a pharmaceutically-acceptable salt thereof, wherein A is an optionally substituted 5- or 6-membered monocyclic aromatic ring containing 1, 2 or 3 ring heteroatoms; B is optionally substituted phenylene or a 6-membered heterocyclic ring containing 1, 2 or 3 nitrogen heteroatoms; R and R 1  are hydrogen or (1-4C)alkyl; n is 1 or 2; R 2  and R 3  are hydrogen, (1-6C)alkyl, (4-7C)cycloalkyl, or (2-6C)alkenyl, or R 2  and R 3  may form along with the nitrogen to which they are attached a 5-, 6- or 7-membered heterocyclic ring, wherein each R 2  or R 3  group or any heterocyclic ring formed from R 2  and R 3  may be optionally substituted with various substituent groups, and wherein Q may be optionally substituted by various substituent groups, which posseses antithrombotic and anticoagulant properties and are accordingly useful in methods of treatment of humans or animals. The invention relates to processes for the preparation of the compounds represented by formula (I), to pharmaceutical compositions containing them, and to their use in the manufacture of medicaments for use in the production of an antithrombotic or anticoagulant effect.

The invention relates to heterocyclic derivatives, orpharmaceutically-acceptable salts thereof, which possess antithiromboticand anticoagulant properties and are accordingly useful in methods oftreatment of humans or animals. The invention also relates to processesfor the preparation of the heterocyclic derivatives, to pharmaceuticalcomposition containing them and to their use in the manufacture ofmedicaments for use in the production of an antithrombotic oranticoagulant effect.

The antithrombotic and anticoagulant effect produced by the compounds ofthe invention is believed to be attributable to their strong inhibitoryeffect against the activated coagulation protease known as Factor Xa.Factor Xa is one of a cascade of proteases involved in the complexprocess of blood coagulation. The protease known as thrombin is thefinal protease in the cascade and Factor Xa is the preceding proteasewhich cleaves prothrombin to generate thrombin.

Certain compounds are known to possess Factor Xa inhibitory propertiesand the field has been reviewed by R. B. Wallis. Current Opinion inTherapeutic Patents, 1993, 1173-1179. Thus it is known that twoproteins, one known as antistatin and the other known as tickanticoagulant protein (TAP), are specific Factor Xa inhibitors whichpossess antithrombotic properties in various animal models of thromboticdisease.

It is also known that certain non-peptidic compounds possess Factor Xainhibitory properties. Of the low molecular weight inhibitors mentionedin the review by R. B. Wallis, all possessed a strongly basic group suchas an amidinophenlyl or amidinonaphthyl group.

We have now found that certain heterocyclic derivatives possess FactorXa inhibitory activity. Many of the compounds of the present inventionalso possess the advantage of being selective Factor Xa inhibitors, thatis the enzyme Factor Xa is inhibited strongly at concentrations of testcompound which do not inhibit or which inhibit to a lesser extent theenzyme thrombin which is also a member of the blood coagulationenzymatic cascade.

The compounds of the present invention possess activity in the treatmentor prevention of a variety of medical disorders where anticoagulanttherapy is indicated, for example in the treatment or prevention ofthrombotic conditions such as coronary artery and cerebro-vasculardisease. Further examples of such medical disorders include variouscardiovascular and cerebrovascular conditions such as myocardialinfarction, the formation of atherosclerotic plaques, venous or arterialthrombosis, coagulation syndromes, vascular injury including reocclusionand restenosis following angioplasty and coronary artery bypass surgery,thrombus formation after the application of blood vessel operativetechniques or after general surgery such as hip replacement surgery, theintroduction of artificial heart valves or on the recirculation ofblood, cerebral infarction, cerebral thrombosis, stroke, cerebralembolism pulmonary embolism, isehaemia and angina (including unstableangina).

The compounds of the invention are also useful as inhibitors of bloodcoagulation in an ex-vivo situation such as, for example, the storage ofwhole blood or other biological samples suspected to contain Factor Xaand in which coagulation is detrimental.

Accordingly in one aspect the present invention provides compounds offormula I

wherein:

A is an optionally substituted 5- or 6-membered monocyclic aromatic ringcontaining 1, 2 or 3 ring heteroatoms selected from oxygen, nitrogen andsulphur;

B is optionally substituted phenylene or a 6-membered heterocyclic ringcontaining 1, 2 or 3 nitrogen heteroatoms.

R and R₁ are independently selected from hydrogen and (1-4C)alkyl,

n is 1 or 2;

R₂ and R₃ are independently selected from hydrogen, (1-6C)alkyl(4-7C)cycloalkyl, (2-6C)alkenyl on R₂ and R₃ may form along with thenitrogen to which they are attached a 5-, 6- or 7-membered heterocyclicring which ma)y contain in addition to the nitrogen atom present 1 or 2additional heteroatoms selected from nitrogen, oxygen and sulphur,wherein each R₂ or R₃ group or any heterocyclic ring formed from R₂ andR₃ may he optionally substituted by hydroxy, amino, carboxy,(1-4C)alkoxycarbonyl, oxo. (1-4)alkyl, hydroxy-(1-4C)alkyl,(1-4C)alkoxy-(1-4C)alkyl, carboxy-(1-4C)alkyl,(1-4C)alkoxycarbonyl-(1-4C)alkyl, or carbamoyl-(1-4C)alkyl;

Q is selected from phenyl, naphthyl, phenyl(1-4C)alkyl,phenyl(2-4C)alkenyl and a 5-, 6- or 7-membered heterocyclic ringcontaining up to 4 heteroatoms selected from nitrogen, oxygen andsulphur wherein Q may be optionally substituted by halo,halo(1-4C)alkyl, cyano, amino, hydroxy, carbamoyl, (1-4C)alkyl,(2-4C)alkenyl, (2-4C)alkynyl, (1-4C)alkoxy, (2-4C)alkenyloxy,(2-4C)alkynyloxy, (1-4C)alkylthio, (1-4C)alkylsulphilnyl,(1-4C)alkylsulphonyl, (1-4C)alkylamino, di(1-4C)alkylamino,(1-4C)alkoxycarbonyl, N-(1-4C)alkylcarbonoyl, (2-6C)alkanoyl,(2-4C)alkanoylamino, hydroxy-(1-4C)alkyl, (1-4C)alkoxy-(1-4C)alkyl,carboxy-(1-4C)alkyl. (1-4C)alkoxycarbonyl-(1-4C)alkyl,carbamoyl-(1-4C)alkyl, N-(1-4C)alkylcarbamoyl-(1-4C)alkyl,N,N-di(1-4C)alkylcarbamoyl-(1-4C)alkyl, phenyl, phenoxy, phenylthio,phenylsulphinyl, phenylsulphonyl, benzyl, benzoyl wherein said phenyl,phenoxy, phenylthio, phenylsulphinyl, phenylsulphonyl, benzyl or benzoylsubstituent bears 1, 2 or 3 substituents selected from halo,trifluoromethyl, cyano, hydroxy, amino, nitro, carboxy, carbamoyl,(1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylamino, di(1-4C)alkylamino.(1-4C)alkoxycarbonyl, N,-(1-4C)alkylcarbamoyl, N,N,(1-4C)alkylcarbamoyland (2-4C)alkanoylamino, or a pharmaceutically acceptable salt thereof.

In this specification the term “alkyl” includes both straight andbranched chain alkyl groups but references to individual alkyl groupssuch as “propyl” are specific for the straight chain version only. Ananalogous convention applies to other generic terms.

It is to be understood that certain heterocyclic derivatives of thepresent invention can exist in solvated as well as unsolvated forms suchas, for example, hydrated forms. It is to be understood that theinvention encompasses all such solvated forms which possess Factor Xainhibitory activity.

It is further to be understood that, insofar as certain of the compoundsof the formula defined above may exist in optically active or racemicforms by virtue of one or more asymmetric carbon atoms, the inventionencompasses any such optically active or racemic form which possessesFactor Xa inhibitory activity. The synthesis of optically active formsmay be carried out by standard techniques of organic chemistry wellknown in the art, for example by synthesis from optically activestarting materials or by resolution of a racemic form.

Preferably A is a pyridyl, pyrimidinyl or pyridazinyl ring for example4-pyridyl, 2-pyridyl, 4-pyridazinyl, 3-pyrimidinyl, 4-pyrimidinyl or3-pyridyl. Of these 4-pyrimidinyl and 4-pyridyl are most preferred.

In one aspect A is unsubstituted. In another aspect A is substituted byone, two or three atoms or groups selected from halo (for examplefluoro, chloro or bromo), oxo, carboxy, trifluoromethyl, cyano, amino,hydroxy, nitro, (1-4C)alkyl (for example methyl or ethyl), (1-4C)alkoxy(for example methoxy or ethoxy), (1-4C)alkoxycarbonyl (1-4C)alkylamino(for example methylamino or ethylamino) or di-(1-4C)alkylamino (forexample dimethylamino or diethylamino). For the avoidance of doubtsubstituents on A may also be present, where possible, on the heteroatomof the ring. Preferred substituents of A are halo, (1-4C)alkyl, aminoand (1-4C)alkylamino.

There are three preferred aspects of ring B:

1. In one aspect B is an optionally substituted 1,4-phenylene ring

2. In one aspect B is an optionally substituted 1,4-piperidinediyl ring,wherein A or the carbonyl group (—CO—) on either side of B is attachedto the nitrogen atom of the ring or B is an optionally substituted1,4-piperazinediyl ring, wherein both A and the carbonyl group (—CO—) oneither side of B are attached to the nitrogen atoms atoms of the ring.

3. In one aspect B is a heterocyclic ring in which neither A nor thecarbonyl group (—CO—) on either side of B are not attached to nitrogenatom(s) of B.

In a preferred aspect heterocyclic rings formed from R₂ and R₃ include1-piperidino, 1-piperazinyl, 4-morpholino, 4-thiomorpholino,1-imidazolidinyl and 1-pyrrolidinyl; preferred substitutions includeoxo, hydroxy, amino and carboxy and include substitutions on any of theadditional heteroatoms, for example 1-oxo-4-thiomorpholino and1,1-dioxo-4-thiomorpholino.

In a preferred aspect R and R₁ are both hydrogen.

A suitable value for Q when it is naphthyl is, for example, 1-naphthylor 2-naphthyl, when it is phenyl-(1-4C)alkyl is, for example, benzyl,phelnylethyl and 3-phelnylpropyl, when it is phenyl-(2-4C)alkenyl is,for example, styryl, cinnamyl or 3-phenylprop-2-enyl: and when it isphenyl-(2-4C)alkynyl is, for example, 2-phenylethynyl,3-phenylprop-2-ynyl and 3-phenylprop-1-ynyl.

A suitable value for Q when it is a heterocyclic moiety containing up to4 heteroatoms selected from nitrogen, oxygen and sulphur is, forexample, a 5- or 6-membered heterocyclic moiety which is a single ringor is fused to one or two benzo rings such as furyl, benzofuranyl,tetrahydrofuryl, chromanyl, thienyl, benzothienyl, pyridyl piperidinyl,quinolyl, 1,2,3,4-tetrahydroquinolinyl, isoquinolyl,1,2,3,4-tetrahydroisoquinolinyl, pyrazinyl, piperazinyl, pyrimidinyl,pyridazinyl, quinoxalinyl, quiniazolinyl, cinnolinyl, pyrrolyl,pyrrolidinyl, indolyl, indolinyl, imidazolyl, benzimildazolyl,pyrazolyl, indazolyl, oxazolyl, benzoxazolyl, isoxazolyl, thiazolyl,benzothilazolyl, isothiazolyl, morpholinol, 4H-1,4-benzoxazinyl,4H-1,4-benzothiazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, oxadiazolyl,furazanyl, thiadiazolyl, tetrazolyl, dibenzofuranyl and dibenzothienyl,which may be attached through any available position including, for anappropriate X₂ group such as, for example, SO₂, C(R⁵)₂ or CO, throughany available nitrogen atom and which may bear up to three substituentsincluding a substituent on any available nitrogen atom.

A suitable value for the heteroaryl substituent on Q or the heteroarylgroup in a heteroaryl-containing substituent on Q which comprises a 5-or 6-membered monocyclic heteroaryl ring containing up to 3 heteroatomsselected from oxygen, nitrogen and sulphur is, for example, furyl,thienyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl,imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,1,2,3-triazolyl, 1,2,4-triazolyl, oxadiazolyl, furazanyl andthiadiazolyl which may be attached through any available positionincluding, through any available nitrogen atom.

Particularly preferred substituents of Q are selected from halo (ideallychloro or bromo) and C₁₋₄alkyl (ideally methyl).

Suitable values for optional substituents for B, Q and for R₂ and R₁are:

for (1-4C)alkyl: methyl ethyl and propyl; 30 for (1-4C)alkoxycarbonylmethoxycarbonyl, ethoxycarbonyl, propoxycarbonyl andtert-butoxycarbonyl; for hydroxy-(1-4C)alkyl: hydroxymethyl,1-hydroxyethyl, 2-hydroxyethyl and 3-hydroxypropyl; for(1-4C)alkoxy-(1-4C)alkyl: methoxymethyl, ethoxymethyl, 1-methoxymethyl,2-methoxyethyl, 2-ethoxyethyl and 3-methoxypropyl; forcarboxy-(1-4C)alkyl: carboxymethyl, 1-carboxyethyl, 2-carboxyethyl and3-carboxypropyl, for (1-4C)alkoxycarbonyl-(1-4C)alkyl:methoxycarbonylmethyl, ethoxycarbonylmethyl, tert-butoxy-carbonylmethyl, 1-methoxycarbonylethyl, 1-ethoxycarbonylethyl,2-methoxycarbonylethyl, 2-ethoxycarbonylethyl, 3-methoxycarbonylpropyland 3-ethoxycarbonylpropyl; for carbamoyl-(1-4C)alkyl carbamoylmethyl,1-carbamoylethyl, 2-carbamoylethyl and 3-carbamoylpropyl;

Suitable values for substituents (where applicable) which may be presenton B, on a heterocyclic or phenyl group within a substituent on Ar, on Qor on a phenyl- or heteroaryl-containing substituent on Q include, forexample:

for halo: fluoro, chloro, bromo; for (1-4C)alkyl: methyl, ethyl, propyl,butyl; for (1-4C)alkoxy: methoxy, ethoxy; for (1-4C)alkylamino:methylamino, ethylamino; for di-(1-4C)alkylamino: dimethylamino,diethylamino; for (2-4C)alkenyl: vinyl and allyl; for (2-4C)alkynyl:ethynyl and prop-2-ynyl; for (2-4C)alkenyloxy: vinyloxy and allyloxy;for (2-4C)alkynyloxy: ethynyloxy and prop-2-ynyloxy; for4-(1-4C)alkylpiperazin-1-yl: 4-methylpiperazin-1-yl and4-ethylpiperazin-1-yl; for (1-4C)alkylthio: methylthio, ethylthio andpropylthio; for (1-4C)alkylsulphinyl: methylsulphinyl, ethylsulphinyland propylsulphinyl; for (1-4C)alkylsulphonyl: methylsulphonyl,ethylsulphonyl and propylsulphonyl; for (2-4C)alkanoylamino: acetamido,propionamido and butyramido; for (1-4C)alkanesulphonamido:methanesulphonamido and ethanesulphonamido; for (1-4C)alkoxycarbonyl:methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl andtert-butoxycarbonyl; for N-(1-4C)alkylcarbamoyl: N-methylcarbamoyl,N-ethylcarbamoyl and N-propylcarbamoyl; forN,N-di-[(1-4C)alkyl]carbamoyl: N,N-dimethylcarbamoyl,N-ethyl-N-methylcarbamoyl and N,N-diethylcarbamoyl; for4-(1-4C)alkylpiperazin-1-ylcarbonyl: 4-methylpiperazin-1-ylcarbonyl and4-ethylpiperazin-1-ylcarbonyl: for (1-4C)alkanesulphonamidocarbonyl:methanesulphonamidocarbonyl and ethanesulphonamidocarbonyl; for(2-4C)alkanoyl: acetyl propionyl and butyryl: for hydroxy-(1-4C)alkyl:hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl and 3-hydroxypropyl: for(1-4C)alkoxy-(1-4C)alkyl: methoxymethyl, ethoxymethyl, 1-methoxymethyl,2-methoxyethyl, 2-ethoxyethyl and 3-methoxypropyl; forcarboxy-(1-4C)alkyl: carboxymethyl, 1-carboxyethyl, 2-carboxyethyl and3-carboxypropyl; for (1-4C)alkoxycarbonyl- (1-4C)alkyl:methoxycarbonylmethyl, ethoxycarbonylmethyl, tert-butoxy-carbonylmethyl, 1-methoxycarbonylethyl, 1-ethoxycarbonylethyl,2-methoxycarbonylethyl, 2-ethoxycarbonylethyl, 3-methoxycarbonylpropyland 3-ethoxycarbonylpropyl; for carbamoyl-(1-4C)alkyl: carbamoylmethyl,1-carbamoylethyl, 2-carbamoylethyl and 3-carbamoylpropyl; forN-(1-4C)alkylcarbamoyl-(1-4C)alkyl: N-methylcarbamoylmethyl,N-ethylcarbamoylmethyl, N-propylcarbamoylmethyl,1-(N-methylcarbamoyl)ethyl, 1-(N-ethylcarbamoyl)ethyl,2-(N-methylcarbamoyl)ethyl, 2-(N-ethylcarbamoyl)ethyl and3-(N-methylcarbamoyl)propyl; for N,N-di-[(1-4C)alkyl]carbamoyl-(1-4C)alkyl: N,N-dimethylcarbamoylmethyl,N-ethyl-N-methylcarbamoylmethyl N,N-diethylcarbamoylmethyl,1-(N,N-dimethylcarbamoyl)ethyl, 1-(N,N-diethylcarbamoyl)ethyl,2-(N,N-dimethylcarbamoyl)ethyl, 2-(N,N-diethylcarbamoyl)ethyl and3-(N,N-dimethylcarbamoyl)propyl;

A preferred class of compounds of the present invention is that wherein:

A is pyridyl, pyrimidinyl or pyridazinyl;

B is 1,4-piperidinediyl, 1,4-piperazinediyl or para-phenylene;

R₂ and R₃ are joined together to form a 6-membered heterocyclic ring,preferably substituted:

Q is styryl or naphthyl optionally substituted by fluoro, chloro orbromo or is phenyl optionally substituted by fluoro, chloro or bromo;

and pharmaceutically-acceptable salts thereof.

Particular compounds of the invention are those listed as Examplesbelow.

A heterocyclic derivative of formula I, or pharmaceutically-acceptablesalt thereof, may be prepared by any process known to be applicable tothe preparation of related compounds. Such procedures are provided as afurther feature of the invention and are illustrated by the followingrepresentative processes in which, unless otherwise stated A, B, X₁, R,R₁, R₂, R₃ and Q have any of the meanings defined hereinbefore whereinany functional group, for example amino, alkylamino, carboxy or hydroxy,is optionally protected by a protecting group which may be removed whennecessary.

Compounds of formula I may be prepared by:

(a) Reacting an acid of formula (II) or a reactive derivative thereof.

 with an amine of formula

R₂R₃NH  (III)

A suitable reactive derivative of an acid of the formula (III) is, forexample, an acyl halide, for example an acyl chloride formed by thereaction of the acid and an inorganic acid chloride, for example thionylchloride; a mixed anhydride, for example an anhydride formed by thereaction of the acid with a chloroformate such as isobutyl chloroformateor with an activated amide such as 1,1-carbonyldiimidazole; an activeester, for example an ester formed by the reaction of the acid and aphenol such as pentafluorophenol, an ester such as pentafluorophenyltrifluoroacetate or an alcohol such as N-hydroxybenzotriazole orN-hydroxysuccinimide, an acyl azide, for example an azide formed by thereaction of the acid and an azide such as diphenylphosphoryl azide; anacyl cyanide, for example a cyanide formed by the reaction of an acidand a cyanide such as diethylphosphoryl cyanide, or the product of thereaction of the acid and a carbodiimide such asN,N′-dicyclolhexylcarbodiimide orN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide.

The reaction is conveniently carried out in the presence of a suitablebase such as, for example, an alkali or alkaline earth metal carbonate,alkoxide, hydroxide or hydride, for example sodium carbonate, potassiumcarbonate, sodium ethoxide, potassium butoxide, sodium hydroxide,potassium hydroxide, sodium hydride or potassium hydride, or anorganometallic base such as an alkyl-lithium, for examplen-butyl-lithium, or a dialkylamino-lithium, for example lithiumdi-isopropylamide, or, for example, an organic amine base such as, forexample, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine,triethiylamine, morpholine or diazabicyclo[5,4,0]undec-7-ene.

The reaction is also preferably carried out in a suitable inert solventor diluent, for example methylenle chloride, chloroform, carbontetrachloride, tetrahydrofuran, 1,2-dimethoxyethane,N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidin-2-one,dimethylsulphoxide or acetone, and at a temperature in the range, forexample, −78° to 150° C., conveniently at or near ambient temperature.

A suitable protecting group for an amino or alkylamino group is, forexample, an acyl group, for example an alkanoyl group such as acetyl, analkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl ortert-butoxycarbonyl group, an arylmethoxycarbonyl group, for examplebenzyloxycarbonyl, or an aroyl group, for example benzoyl. Thedeprotection conditions for the above protecting groups necessarily varywith the choice of protecting group. Thus, for example, an acyl groupsuch as an alkanoyl or alkoxycarbonyl group or an aroyl group may beremoved for example, by hydrolysis with a suitable base such as analkali metal hydroxide, for example lithium or sodium hydroxide.Alternatively an acyl group such as a tert-butoxycarbonyl group may beremoved, for example, by treatment with a suitable acid such ashydrochloric, sulphuric or phosphoric acid or trifluoroacetic acid andan arylmethoxycarbonyl group such as a benzyloxycarbonyl group may beremoved, for example, by hydrogenation over a catalyst such aspalladium-on-carbon, or by treatment with a Lewis acid for example borontris(trifluoroacetate). A suitable alternative protecting group for aprimary amino group is, for example, a phthaloyl group which may beremoved by treatment with an alkylamine, for exampledimethylaminopropylamine, or with hydrazine.

A suitable protecting group for a hydroxy group is, for example, an acylgroup, for example an alkanoyl group such as acetyl, an aroyl group, forexample benzoyl or an arylmethyl group, for example benzyl. Thedeprotection conditions for the above protecting groups will necessarilyvary with the choice of protecting group. Thus, for example, an acylgroup such as an alkanoyl or an aroyl group may be removed, for example,by hydrolysis with a suitable base such as an alkali metal hydroxide,for example lithium or sodium hydroxide. Alternatively an arylmethylgroup such as a benzyl group may be removed, for example, byhydrogenation over a catalyst such as palladium-on-carbon.

A suitable protecting group for a carboxy group is, for example, anesterifying group, for example a methyl or an ethyl group which may beremoved, for example, by hydrolysis with a base such as sodiumhydroxide, or for example a tert-butyl group which may be removed, forexample, by treatment with an acid, for example an organic acid such astrifluoroacetic acid, or for example a benzyl group which may beremoved, for example, by hydrogenation over a catalyst such aspalladium-on-carbon.

(b) Reacting an acid of formula (IV), or a reactive derivative thereof,

A—B—COOH  (IV)

 with an amine of formula (V)

Suitable reactive derivatives of an acid of the formula (IV) andconditions are described in process method (a) above.

(c) Coupling a compound of formula (VI)

 with a compound of formula

Z—SO₂—Q  (VII)

 wherein Z is a displaceable group such as halo, in conditions similarto those described in process method (a) above.

(d) For compounds of formula I, wherein A is attached to B by an alkylbond, by coupling a compound of formula (VIII)

 wherein Z is a displaceable group such as halo, with an activatedderivative of heterocyclic ring A. Suitable activated derivativesinclude metalised derivatives such as with zinc or tin and boranederivatives. The activated derivative of heterocyclic ring A is reactedwith a compound of formula (VII) to effect cross coupling where Z is ahalo group, such as iodo. bromo or chloro, or triflate. Suitably thereaction is catalysed by use of a transition state metal catalyst, suchas palladium, e.g. tetrakis (triphenylphosphine) palladium (0).

Alternatively it is possible that ring A contains the displaceable groupZ and ring B is activated and the reaction performed as described above.

(e) For compounds of formula I, wherein A is attached to B by an alkylbond, by forming A ring on compounds of formula (VIII), wherein Z is afunctional group capable of cyclisation. Suitable reagents andconditions are described below in the preparation of compounds offormula (IV) by cyclisation.

(f) For compounds of formula I, wherein A is attached to B by an amidebond, by reacting an amine of formula (VIII), wherein Z is hydrogen,with a derivative of heterocyclic ring A containing a suitabledisplaceable group, such as halo, in the presence of a base inconditions similar to those described in process method (a) above.

(g) Oxidation of a compound of formula (IX)

 wherein Y is S or SO.

A suitable oxidising agent is, for example, any agent known in the artfor the oxidation of thio to sulphinyl and/or sulphonyl, for example,hydrogen peroxide, a peracid (such as 3-chloroperoxybenzoic orperoxyacetic acid), an alkali metal peroxysulphate (such as potassiumperoxymonosulphate), chromium trioxide or gaseous oxygen in the presenceof platinum. The oxidation is generally carried out under as mildconditions as possible and with the required stoichiometric amount ofoxidising agent in order to reduce the risk of over oxidation and damageto other functional groups. In general the reaction is carried out in asuitable solvent or diluent such as methylene chloride, chloroform,acetone, tetrahydrofuran or tert-butyl methyl ether and at atemperature, for example, at or near ambient temperature, that is in therange 15 to 35° C. Those compounds of formula (IX) which contain oxygenlabile groups (such as A ring is pyridyl) are probably not suitableintermediates for this process step, unless oxidation of such groups isdesired.

Compounds of formula (II) may he prepared by reacting a n acid offormula (IV), as defined above, with an amine of formula (X)

wherein P, including the carboxy group to which it is attached, is asuitable protecting group such as an alkoxy ester, for exampleethoxycarbony; in an analogous method as described in process method (b)above, and subsequently conversion to the acid compound of formula (II)by deesterification.

Compounds of formula (IV) may be prepared by coupling of the B ring tothe A ring as described in alternative process steps (d) and (f). For acoupling of A to B, via an alkyl bond, one ring is activated and theother contains a suitable displaceable group. Ideally the reaction iscatalysed, such as with a palladium catalyst. Suitable reagents andconditions are described in a review article Harvey R. G. OrganicPreparations and Procedures International, Vol. 29, (1997), 139.

Activated derivatives of heterocyclic ring A or B include metalisedderivatives, such as with zinc or tin, borane derivatives and stannylderivatives. Formation of the activated form desired is typically bysubstitution reactions. The activating group is added to the ring inplace of a suitable leaving group or atom, such as halo or triflate.Suitable reagents and conditions are described in Shikara M. et.al.;Chem. Pharm. Bull.; 33(11), 4755-4763 (1985); Sandosham J. et.al.;Hetrerocycles, Vol. 37, No. 1, p501, (1994); and Salamoto T. et.al.;Tetrahedron: Vol. 49, No. 43, 9713-9720, (1993).

Alternatively compounds of formula (IV) may be prepared as described inprocess variant (e) above by forming A ring on the B ring containing asuitable functional group for cyclisaton. Suitable reagents andconditions are described in Bredereck H. Chem. Ber.; 96, 1505, (1963);Fuchigami. T., Bull. Chem. Soc. Jpn. 49, p3607, (1976); Huffman. K. R.,J. Org. Chem., 28, p1812, (1963); Palusso, G., Gazz, Chim. Ital., 90,p1290, (1960) and Ainsworth C. J., Heterocycl. Chem., 3, p470, (1966).Processes suitable for synthesis of starting materials in suchcyclisation reactions are described in Zhang M. Q. et.al; J.Heterocyclic. Chem.; 28, 673, (1991 ) and Kosugi. M, et. al., Bull.Chem. Soc. Jpn., 60, 767-768 (1987).

Compounds of formula (XII) may be prepared via ring formation, such asdescribed in Church R, et.al.: J. Org. Chem., 60, 3750-3758, (1995) andFalck-Penderson M. L. et.al.; Acta Chem. Scand., 47, 63-67, (1993).Compounds formed by such reactions are also suitable starting materialsfor preparation of activated derivatives of the heterocyclic ring A bysubstitution reaction, as described above.

Compounds of formula (V) may be prepared by reacting an acid of formula(XI)

wherein P is a protecting group, with an amine of formula (III), asdefined above, in an analogous manner as described in method (a) above,and subsequently removing the protecting group.

Compounds of formula (VI) may be prepared from the amino acid of formula(XII)

by performing both reactions (a) and (b) described above, in eitherorder, with the use of suitable protecting groups as described above.

Compounds of formula (VII) may be prepared by conversion of the thioanalogue of the compound of formula (XIII), wherein Z is a dispaceablegroup

to the sulphonic acid halide by reactions as described in Kharasch N.Et.al.; J. Am. Chem. Soc., 73, p3240, 1951. Suitable reactions for thepreparation of the thio analogues of compounds of formula (VII) aredescribed in Newman M. S. et.al.; Organic synthesis. Vol. 51, p139.

Compounds of formula (VIII) may be prepared from compounds of formula(XI), as defined above, by performing reaction (a) described above andreacting the product with an acid of formula

Z—B—COOH  (XIV)

in conditions similar to those described for reaction (b) above.

Compounds of formula (IX) may be prepared by an analagous reaction forthe preparation of compounds of formula I using, method (c) above,reacting, a compound of formula (VI), as defined above, with a compoundof formula (XIII), as defined above.

When a pharmaceutically-acceptable salt of compound of the formula I isrequired, it may be obtained, for example, by reaction of said compoundwith a suitable acid or base using a conventional procedure.

When an optically active form of a compound of the formula I isrequired, it may be obtained, for example, by carrying out one of theaforesaid procedures using an optically active starting material or byresolution of a racemic form of said compound using a conventionalprocedure.

As stated previously, the compounds of the formula I are inhibitors ofthe enzyme Factor Xa. The effects of this inhibition may be demonstratedusing one or more of the standard procedures set out hereinafter:

a) Measurement of Factor Xa Inhibition

An in vitro assay system is carried out based on the method of Kettneret al., J. Biol. Chem., 1990, 265, 18289-18297, whereby variousconcentrations of a test compound are dissolved in a pI7.5 buffercontaining 0.5% of a polyethylene glycol (PEG 6000) and incubated at 37°C. with human Factor Xa (0.001 Units/ml. 0.3 ml) for 15 minutes. Thechromogenic substrate S-2765 (KabiVitrum AB, 2 μM) is added and themixture is incubated at 37° C. for 20 minutes whilst the absorbance at405 lime is measured. The maximum reaction velocity (Vmax) is determinedand compared with that of a control sample containing no test compound.Inhibitor potency is expressed as an IC₅₀ value.

b) Measurement of Thrombin Inhibition

The procedure of method a) is repeated except that human thrombin (0.005Units/ml) and the chromogenic substrate S-2238 (KabiVitrum AB, 7 μM) areemployed.

c) Measurement of Anticoagulant Activity

An in vitro assay whereby human, rat or rabbit venous blood is collectedand added directly to a sodium citrate solution (3.2 g/100 ml. 9 partsblood to 1 part citrate solution). Blood plasma is prepared bycentrifugation (1000 g, 15 minutes) and stored at 2-4° C. Conventionalprothrombin time (PT) tests are carried out in the presence of variousconcentrations of a test compound and the concentration of test compoundrequired to double the clotting time, hereinafter referred to as CT2, isdetermined. In the PT test, the test compound and blood plasma areincubated at 37° C. for 10 minutes. Tissue thromboplastin with calcium(Sigma Limited, Poole, England) is added and fibrin formation and thetime required for a clot to form are determined.

(d) Rat Disseminiated Intravascular Coagulation in vivo Activity Test

Fasted male Alderley Park rats (300-450 g) are pre-dosed by oral gavage(5 mls/kg) with compound or vehicle (5% DMSO/PEG200) at various timesbefore being anaesthetised with Initraval® (120 mg/kg i.p.). The leftjugular vein and the right carotid artery are exposed and cannulated. A1 mL blood sample is taken from the carotid canular into 3.2% trisodiumcitrate, 0.5 mL of the whole blood is then treated with EDTA and usedfor platelet count determination whilst the remainder is centrifuged (5mins, 20000 g) and the resultant plasma frozen for subsequent druglevel, fibrinogen or thrombin antithrombin (TAT) complex determinations.Recombinant human tissue factor (Dade Innovin Cat.B4212-50),reconstituted to the manufacturers specification, is infused (2mL/kg/hr) into the venous canular for 60 minutes. Immediately after theinfusion is stopped a 2 mL blood sample is taken and platelet count,drug level, plasma fibrinogen concentration and TAT complex aredetermined as before. Platelet counting is performed using a CoulterT540 blood analyser. Plasma fibrinogen and TAT levels are determiningusing a clotting assay (Sigma Cat.880-B) and TAT ELISA (Behring)respectively. The plasma concentration of the compound is bioassayedusing human Factor Xa and a chromogenic substrate S2765 (Kabi),extrapolated from a standard curve (Fragmin) and expressed inAnti-Factor Xa units. The data is analysed as follows: tissuefactor-induced reductions in platelet count are normalised with respectto pre-dose platelet count and drug activity expressed as a percentinhibition of tissue factor-induced thrombocytopenia when compared tovehicle treated animals. Compounds are active if there is statisticallysignificant (p<0.05) inhibition of TF-induced thrombocytopenia.

e) An ex vivo Assay of Anticoagulant Activity

The test compound is administered intravenously or orally to a group ofAlderley Park Wistar rats. At various times thereafter animals areanaesthetised, blood is collected and PT coagulation assays analogous tothose described hereinbefore are conducted.

According to a further feature of the invention there is provided apharmaceutical composition which comprises a heterocyclic derivative ofthe formula I, or a pharmaceutically-acceptable salt thereof, inassociation with a pharmaceutically-acceptable diluent or carrier.

The composition may be in a form suitable for oral use, for example atablet, capsule, aqueous or oily solution, suspension or emulsion; fortopical use, for example a cream, ointment, gel or aqueous or oilysolution or suspension; for nasal use, for example a snuff, nasal sprayor nasal drops: for vaginal or rectal use, for example a suppository;for administration by inhalation, for example as a finely divided powdersuch as a dry powder, a microcrystalline form or a liquid aerosol; forsub-lingual or buccal use, for example a tablet or capsule; or forparenteral use (including intravenous, subcutaneous. intramuscular,intravascular or infusion), for example a sterile aqueous or oilysolution or suspension. In general the above compositions may beprepared in a conventional manner using, conventional excipients.

The amount of active ingredient (that is a heterocyclic derivative ofthe formula I, or a pharmaceutically-acceptable salt thereof) that iscombined with one or more excipients to produce a single dosage formwill necessarily vary depending upon the host treated and the particularroute of administration. For example, a formulation intended for oraladministration to humans will generally contain, for example, from 0.5mg to 2 g of active agent compounded with an appropriate and convenientamount of excipients which may vary from about 5 to about 98 percent byweight of the total composition. Dosage unit forms will generallycontain about 1 mg to about 500 mg of an active ingredient.

According to a further feature of the invention there is provided aheterocyclic derivative of formula I, or a pharmaceutically acceptablesalt thereof, for use in medical therapy.

According to a further feature of the invention there is provided aheterocyclic derivative of formula I, or a pharmaceutically-acceptablesalt thereof, for use in a method of treatment of the human or animalbody by therapy.

The invention also includes the use of such an active ingredient in theproduction of a medicament for use in:

(i) producing a Factor Xa inhibitory effect;

(ii) producing an anticoagulant effect;

(iii) producing an antithrombotic effect;

(iv) treating a Factor Xa mediated disease or medical condition;

(v) treating a thrombosis mediated disease or medical condition;

(vi) treating coagulation disorders: and/or

(vii) treating thrombosis or embolism involving Factor Xa mediatedcoagulation.

The invention also includes a method of producing an effect as definedhereinbefore or treating a disease or disorder as defined hereinbeforewhich comprises administering to a warm-blooded animal requiring suchtreatment an effective amount of an active ingredient as definedhereinbefore.

The size of the dose for therapeutic or prophylactic purposes of acompound of the formula I will naturally vary according to the natureand severity of the medical condition the age and sex of the animal orpatient being treated and the route of administration, according to wellknown principles of medicine. As mentioned above, compounds of theformula I are useful in the treatment or prevention of a variety ofmedical disorders where anticoagulant therapy is indicated. In using acompound of the formula I for such a purpose, it will generally beadministered so that a daily dose in the range, for example, 0.5 to 500mg/kg body weight is received, given if required in divided doses. Ingeneral lower doses will be administered when a parenteral route isemployed. for example a dose for intravenous administration in therange, for example, 0.5 to 50 mg/kg body weight will generally be used.For preferred and especially preferred compounds of the invention, ingeneral, lower doses will he employed, for example a daily dose in therange, for example, 0.5 to 10 mg/kg body weight.

Although the compounds of the formula I are primarily of value astherapeutic or prophylactic agents for use in warm-blooded animalsincluding man, they are also useful whenever it is required to producean anticoagulant effect, for example during the ex-vivo storage of wholeblood or in the development of biological tests for compounds leavinganticoagulant properties.

The compounds of the invention may be administered its a sole therapy orthey may be administered in conjunction with other pharmacologicallyactive agents such as a thrombolytic agent, for example tissueplasminogen activator or derivatives thereof or streptokinase. Thecompounds of the invention may also be administered with, for example, aknown platelet aggregation inhibitor (for example aspirin, a thromboxaneantagonist or a thromboxane synthase inhibitor), a known hypolipidaemicagent or a known anti-hypertensive agent.

EXAMPLE 11-(1,1-Dioxothiomorpholino-4-carbonyl)-1-[1-(4-pyridyl)piperazin-4-ylcarbamoyl]-2-(bromonaphth-2-ylsulphonamido)ethane

To a stirred suspension of A, prepared as in Example 2, (1.00 g, 1.548mmole) in chloroform (50 ml) at room temperature was addedmetachloroperbenzoic acid (1.597 g, 4.644 mmole, 3 equivalents). Ayellow gum formed. This gum was washed with dichloromethane (150 ml) andthen with water (100 ml). The resulting yellow solid was triturated withether and was dried in vacuo to give a pale yellow solid. This materialwas chromatographed on an alumina bond elute column, eluting withdichloromethane with increasing concentrations of methanol from 0% to5%. The required product was eluted with 2% to 3% methanol indichloromethane. Evaporation of these fractions yielded the product as acolourless solid (0.30 g, 28%).

NMR (300 MHz, DMSO) 1.4-1.6(m,2H): 1.6-1.7(m,2); 2.3-2.4(m,1H);2.7-2.8(m,2H); 2.9-3.3(m,5H); 3.7-4.0(m,6H); 4.7-4.9(m,1H);6.7-6.8(m,2H); 7.7-7.9(m,3H); 8.0-8.2(m,5H); 8.3(s,1H); 8.5(s,1H); MSES− (mH)+ 678.

EDAC (10.283 g, 53.6 mmole) was added to a solution of B (35 g, 44.7mmole), thiomorpholine sulphone trifluoroacetate (13.36 g, 53.6 mmole),n-hydroxybenztriazole (9.052 g, 67 mmole) and triethylamine(6.94 ml) inDMF (500 ml). Stirring was continued overnight. The mixture was pouredinto water (3.5 litres) and basified to pH8 with aqueous sodiumhydroxide (2M). A white solid precipitated which was filtered off. Thesolid was dissolved in a mixture of dichloromethane and methanol (1:1 byvolume). The resulting solution was boiled on the steam bath to reducethe volume until the solution became slightly cloudy. On cooling therequired product separated as colourless crystals. The product wasfiltered off, washed with ether and dried.

The starting materials were prepared as follows;

Sodium hydroxide (1M, 38.7 ml, 38.7 mmole) was added to a stirredsolution of C (7.42 g, 12.9 mmole) in methanol (77 ml). After 1 hour theresulting solution was warmed and boiled under reflux for 0.75 hour, andthen was allowed to cool to room temperature and stirred for a further 1hour. The solution was acidified with 2M hydrochloric acid, and wasevaporated in vacuo to yield B as a colourless solid (8.83 g, 82%).

MS ESP− (m-H)− 559.

Thionyl chloride (10.54 ml, 144.6 mmole) was added to a stirredsuspension of N-(4-pyridyl)piperidine-4-carboxylic acid (3.7245 g, 18.08mmole) in dichloromethane (50 ml). Stirring was continued for 2 hours.The solvent was evaporated in vacuo and the residue re-evaporated fromdichloromethane (3×50 ml) to leave the product E. A solution of thisacid chloride in dichloromethane (50 ml) was added slowly to a stirredsolution D chloride (7.0 g, 18.08 mmole) and triethylamine (7.546 ml,54.2 mmole) in dichloromethane, and the resulting mixture was stirredovernight. The solution was poured into water (500 ml) and the resultingmixture was extracted with dichloromethane (3×100 ml). The combinedextracts were dried over magnesium sulphate and evaporated to leave ayellow oil, This was chromatographed on a column of deactivated alumina(100 g), cluing with dichloromethane containing 1%, 2% and finally 3%methanol by volume. The fractions containing the required product C wereevaporated in vacuo to afford a pale yellow foam (7.42 g, 71%).

NMR (300 MHz,DMSO) 14-15(m,2H); 1.6-1.7(m,2H); 2.3-2.4(m,1H);2.7-2.9(m,2H); 3.1-3.2(m,2H); 3.55(s,3H); 3.8-3.9(m,2H); 4.3-4.4(m,1H);6.75(d,2H); 7.75-7.85(m,2H); 7.9-8.0(m,1H); 8.1-8.2(m,5H); 8.35(s,1H);8.45(s,1H). MS ESP+ (mH)+ 575.

A solution of 6-bromonaphthalene-2-sulphonyl chloride (19.17 g, 71mmole) in dichloromethane (150 ml) was added over 0.5 hour to a stirredmixture of methyl 2,3-diaminiopropionate dihydrochloride (13.561 g, 71mmole) and triethylamine 29.63 ml, 213 mmole) in dichloromethane (400ml) at 0C. The solid gradually dissolved. The mixture was stirred at 0°C. for 1 hour and overnight at room temperature. The yellow solution waswashed with water (2×350 ml). The combined extracts were dried overmagnesium sulphate, and the solvent evaporated in vacuo to leave a brownresidue. This was dissolved in methanol (500 ml) and hydrogen chloridein ether (1100 ml, 1M) was added. The solution was stirred for 1 hour,and was then evaporated in vacuo to leave a brown solid. Ethyl acetate(300 ml) was added and the mixture warmed to reflux. The brown solidchanged in appearance to a colourless solid. The suspension was cooledand stirred at 0° C. for 10 minutes. The required product D was filteredoff (16.26 g, 54%).

NMR (300 MHz., DMSO) 3.2-3.3(m,2H); 3.7(s,3H); 4.1(t,1H); 7.8(dd,1H);7.9(dd,1H); 8.15(d,2H); 8.35(s,1H); 8.5(s,1H); 8.6-8.8(m,3H). MS ESP+(mnH)+ 387.

Thionyl chloride (22 ml) was added over 10 minutes to methanol (36 ml)at −5° C. with stirring. After stirring for a further 5 minutes at −5°C., 2,3-diaminopropionic acid monohydrochloride (10 g, 71 mmole) wasadded. The mixture was stirred at −5° C. for 3 hours, at which time allof the solid had dissolved. After stirring at room temperature for 2hours, the solution was boiled under reflux for 1.5 hours, and was stoodat room temperature overnight. Evaporation of the solvent in vacuoafforded the required product as colourless crystals (13.561, 100%).

NMR (300 MHz., DMSO) 3.2-3.4(m,2H); 3.7(s,3H); 4.4(t,1H); 8.6-9.2(m,6H).MS ESP+ (mH)+ 119.

A solution of N-tert-butyloxycarbonyl thiomorpholine sulphone (14.805 g,63 mmole) in trifluoroacetic acid (100 ml) was stirred at roomtemperature for 45 minutes. Evaporation of the solvent in vacuo affordeda yellow oil, which was dissolved in ether (500 ml). The requiredproduct separated as colourless crystals, which were filtered off,washed with ether (75 ml) and dried in vacuo. The yield was 17.55 g,100%.

NMR (300 MHz, CDCl3) 3.4-3.5(m,4H); 3.5-3.6(m,4H).

A solution of metachlorobenzoic acid (55%, 21.7 g) in chroroform (100ml) and dichloromethane (100 ml) was added gradually over 40 minutes toa stirred solution of N-tert-butyloxycarbonyl thiomorpholine (6.4 g,31.5 mmole) in chloroform (500 ml) kept below 20° C. The cooling bathwas removed and the mixture was stirred at room temperature for 1 hour.The mixture was washed with aqueous sodium hydroxide(2M, 2×300 ml) andwater (300 ml). The organic solution was dried over magnesium sulphateand the solvent evaporated in vacuo to yield the required product as acolourless solid (7.50 g, 100%).

NMR (300 MHz,CDCl3) 1.5(s,9H); 2.9-3.1(m,4H); 3.8-4.0(m,4H).

A solution of BOC—O—BOC (28.34 g, 0.13 Mole) in dichloromethane (100 ml)was added over 15 minutes to a solution thiomorpholine (13.05 ml, 0.13Mole) and triethylamine (20.87 ml, 0.15 Mole) in dichloromethane (600ml). The mixture was stirred for 1 hour. Vigorous evolution of carbondioxide occurred. Ether (600 ml) was added and the organic solution waswashed with citric acid (3×300 ml 1M), water (3×300 ml), brine (300 ml),dried over magnesium sulphate, and evaporated in vacuo to giveN-tert-butyloxycarbonyl thiomorpholine as a colourless solid (26.5 g,100%).

NMR (300 MHz,CDCl3) 1.4(s,9H); 2.5-2.6(m,4H); 3.6-3.65(m,4H). MS ESP+(mH)+ 204.

EXAMPLE 21-(Thiomorpholino-4-carbonyl)-1-[1-(4-pyridyl)piperidine-4-ylcarbamoyl]-2-(bromonaphth-2-ylsulphonamido)ethane

To a stirred solution of B (2.5 g, 3.652 mmole), thiomorpholine (0.442ml, 4.38 mmole) and N-hydroybenztriazole (0.7395 g, 5.478 mmole) in DMT(20 ml) was added EDAC (0.840 g, 4.38 mmole). The solution was stirredovernight, and was then was poured into water (300 ml). This aqueoussolution was adjusted to pH 12 by the addition of aqueous sodiumhydroxide, and extracted with ethyl acetate (3×200 ml). The combinedorganic extracts were washed with water (300 ml), brine (100 ml), driedwith magnesium sulphate, and the solvent evaporated to yield therequired product as a pale yellow solid (2.21 g, 94%).

NMR (300 MHz, DMSO) 1,4-1.5(m,2H); 1.6-1.7(m,2H); 2.3-2.5(m,2H);2.7-2.9(m,3H); 3.0-3.1(m,1H); 3.6-3.9(m,8H); 4.7-4.8(m,1H); 6.75(d,2H);7.8(d,1H); 7.85(d,1H); 8.1-8.2(m,5H); 8.3(s,1H); 8.5(s,1H). MS ESP+(mH)+ 646.

EXAMPLE 3

Using similar procedures as described in Example 2 the following wereprepared, but starting with piperidine and morpholine respectively inplace of thiomorpholine.

No R NMR (300 MHz, DMSO) 1 CH₂ 1.3-1.7 (m, 10H); 2.3-2.45 (m, 1H);2.7-2.95 (m, 3H); 3.0-3.1 (m, 1H); 3.2-3.5 (m, 4H); 3.8-3.9 (m, 2H);4.7-4.85 (m, 1H); 6.7-6.8 (m, 2H); 7.7-7.9 (m, 4H); 8.0-8.2 (m, 4H); 8.3(s, 1H); 8.45 (s, 1H) MS ESP + (mH) + 628 2 O 1.4-1.5 (m, 2H); 1.6-1.7(m, 2H); 2.3-2.4 (m, 1H); 2.5-3.0 (m, 4H); 3.0-3.1 (m, 1H); 3.2-3.6 (m,7H); 3.8-3.9 (m, 2H); 4.7-4.8 (m, 1H); 6.7-6.8 (m, 2H); 7.7-7.9 (m, 3H);8.0-8.2 (m, 5H); 8.3 (s, 1H); 8.5 (s, 1H) MS ESP + (mH) + 630

What is claimed is:
 1. A compound of formula I, or apharmaceutically-acceptable salt thereof,

wherein: A is a 5- or 6-membered monocyclic aromatic ring containing 1,2 or 3 ring heteroatoms selected from oxygen, nitrogen and sulphurwherein A may be optionally substituted by one, two or three atoms orgroups selected from halo, oxo, carboxy, trifluoromethyl, cyano, amino,hydroxy, nitro, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkoxycarbonyl and,(1-4C)alkylamino or di-(1-4C)alkylamino; B is a phenylene or a6-membered heterocyclic ring containing 1, 2 or 3 nitrogen heteroatomswherein B may be optionally substituted by halo, (1-4C)alkyl,(1-4C)alkoxy, (1-4C)alkylaminoethylamino, di-(1-4C)alkylamino,(2-4C)alkenyl, (2-4C)alkynyl, (2-4C)alkenyloxy, (2-4C)alkynyloxy,4-(1-4C)alkylpiperazin-1-yl, (1-4C)alkylthio, (1-4C)alkylsulphinyl,(1-4C)alkylsulphonyl, (2-4C)alkanoylamino, (1-4C)alkanesulphonamido,(1-4C)alkoxycarbonyl, N-(1-4C)alkylcarbamoyl,N,N-di-[(1-4C)alkyl]carbamoyl, 4-(1-4C)alkylpiperazin-1-ylcarbonyl,(1-4C)alkanesulphonamidocarbonyl, (2-4C)alkanoyl, hydroxy-(1-4C)alkyl,(1-4C)alkoxy-(1-4C)alkyl, carboxy-(1-4C)alkyl,(1-4C)alkoxycarbonyl-(1-4C)alkyl, carbamoyl-(1-4C)alkyl,N-(1-4C)alkylcarbamoyl-(1-4C)alkyl, orN,N-di-[(1-4C)alkyl]carbamoyl-(1-4C)alkyl; R and R₁ are independentlyselected from hydrogen and (1-4C)alkyl; n is 1 or 2; R₂ and R₃, incombination with the nitrogen to which they are attached, form a6-membered heterocyclic ring which may have in addition to the nitrogenatom 1 or 2 heteroatoms selected from nitrogen, oxygen and sulphur,wherein the heterocyclic ring formed from R₂ and R₃ may be optionallysubstituted by hydroxy, amino, carboxy, (1-4C)alkoxycarbonyl, oxo,(1-4C)alkyl, hydroxy-(1-4C)alkyl, (1-4C)alkoxy-(1-4C)alkyl,carboxy-(1-4C)alkyl, (1-4C)alkoxycarbonyl-(1-4C)alkyl, orcarbamoyl-(1-4C)alkyl; and Q is selected from phenyl, naphthyl,phenyl(1-4C)alkyl, phenyl(2-4C)alkenyl and a 5-, 6- or 7-memberedheterocyclic ring containing up to 4 heteroatoms selected from nitrogen,oxygen and sulphur wherein Q may be optionally substituted by halo,halo(1-4C)alkyl, cyano, amino, hydroxy, carbamoyl, (1-4C)alkyl,(2-4C)alkenyl, (2-4C)alkynyl, (1-4C)alkoxy, (2-4C)alkenyloxy,(2-4C)alkynyloxy, (1-4C)alkylthio, (1-4C)alkylsulphinyl,(1-4C)alkylsulphonyl, (1-4C)alkylamino, di(1-4C)alkylamino,(1-4C)alkoxycarbonyl, N-(1-4C)alkylcarbonoyl, (2-6C)alkanoyl,(2-4C)alkanoylamino, hydroxy-(1-4C)alkyl, (1-4C)alkoxy-(1-4C)alkyl,carboxy-(1-4C)alkoxycarbonyl-(1-4C)alkyl, carbamoyl-(1-4C)alkyl,N-(1-4C)alkylcarbamoyl-(1-4C)alkyl,N,N-di(1-4C)alkylcarbamoyl-(1-4C)alkyl, phenyl, phenoxy, phenylthio,phenylsulphinyl, phenylsulphonyl, benzyl, or benzoyl, wherein saidphenyl, phenoxy, phenylthio, phenylsulphinyl, phenylsulphonyl, benzyl orbenzoyl substituent bears 1, 2 or 3 substituents selected from halo,trifluoromethyl, cyano, hydroxy, amino, nitro, carboxy, carbamoyl,(1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylamino, di(1-4C)alkylamino,(1-4C)alkoxycarbonyl, N,-(1-4C)alkylcarbomoyl, N,N,(1-4C)alkylcarbamoyland (2-4C)alkenoylamino.
 2. The compound of formula I as claimed inclaim 1, wherein B is a 1,4-piperidinediyl or 1,4-piperazinediyl ring.3. The compound of formula I as claimed in claim 1 or claim 2 wherein Qis naphthyl.
 4. The compound of formula I as claimed in claim 3 whereinQ is substituted by halo or (1-4C)alkyl.
 5. The compound of formula I asclaimed in claim 1 or claim 2 wherein A is 4-pyrimidinyl or 4-pyridyl.6. The compound of formula I as claimed in claim 5 wherein A issubstituted by a substituent selected from halo, (1-4C)alkyl, amino and(1-4C)alkylamino.
 7. A pharmaceutical composition comprising a compoundof formula I, as defined in claim 1 or claim 2, and a pharmaceuticallyacceptable diluent or carrier.
 8. A method for the treatment of adisease or medical condition mediated by Factor Xa comprisingadministering to a warm-blooded animal in need thereof atreatment-effective amount of a compound as defined in claim 1 or claim2.
 9. A method for the inhibition of Factor Xa in a warm-blooded animalin need thereof comprising administering to said animal a Factor Xainhibiting amount of a compound as defined in claim 1 or claim
 2. 10. Amethod for the treatment of cardiovascular or cerebrovascular disease ina warm-blooded animal in need thereof comprising administering to saidanimal a treatment-effective amount of a compound as defined in claim 1or claim 2.